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December 15, 2003

By Daniel C. Javitt and Joseph T. Coyle

Today the word "schizophrenia" brings to mind such names as John Nash and Andrea Yates. Nash, the subject of the Oscar-winning film A Beautiful Mind, emerged as a mathematical prodigy and eventually won a Nobel Prize for his early work, but he became so profoundly disturbed by the brain disorder in young adulthood that he lost his academic career and floundered for years before recovering. Yates, a mother of five who suffers from both depression and schizophrenia, infamously drowned her young children in a bathtub to "save them from the devil" and is now in prison.

The experiences of Nash and Yates are typical in some ways but atypical in others. Of the roughly 1 percent of the world's population stricken with schizophrenia, most remain largely disabled throughout adulthood. Rather than being geniuses like Nash, many show below- average intelligence even before they become symptomatic and then undergo a further decline in IQ when the illness sets in, typically during young adulthood. Unfortunately, only a minority ever achieve gainful employment. In contrast to Yates, fewer than half marry or raise families. Some 15 percent reside for long periods in state or county mental health facilities, and another 15 percent end up incarcerated for petty crimes and vagrancy. Roughly 60 percent live in poverty, with one in 20 ending up homeless. Because of poor social support, more individuals with schizophrenia become victims than perpetrators of violent crime.

Medications exist but are problematic. The major options today, called antipsychotics, stop all symptoms in only about 20 percent of patients. (Those lucky enough to respond in this way tend to function well as long as they continue treatment; too many, however, abandon their medicines over time, usually because of side effects, a desire to be "normal" or a loss of access to mental health care). Two thirds gain some relief from antipsychotics yet remain symptomatic throughout life, and the remainder show no significant response.

An inadequate arsenal of medications is only one of the obstacles to treating this tragic disorder effectively. Another is the theories guiding drug therapy. Brain cells (neurons) communicate by releasing chemicals called neurotransmitters that either excite or inhibit other neurons. For decades, theories of schizophrenia have focused on a single neurotransmitter: dopamine. In the past few years, though, it has become clear that a disturbance in dopamine levels is just a part of the story and that, for many, the main abnormalities lie elsewhere. In particular, suspicion has fallen on deficiencies in the neurotransmitter glutamate. Scientists now realize that schizophrenia affects virtually all parts of the brain and that, unlike dopamine, which plays an important role only in isolated regions, glutamate is critical virtually everywhere. As a result, investigators are searching for treatments that can reverse the underlying glutamate deficit.

Multiple Symptoms
To develop better treatments, investigators need to understand how schizophrenia arises--which means they need to account for all its myriad symptoms. Most of these fall into categories termed "positive," "negative" and "cognitive." Positive symptoms generally imply occurrences beyond normal experience; negative symptoms generally connote diminished experience. Cognitive, or "disorganized," symptoms refer to difficulty maintaining a logical, coherent flow of conversation, maintaining attention, and thinking on an abstract level.

The public is most familiar with the positive symptoms, particularly agitation, paranoid delusions (in which people feel conspired against) and hallucinations, commonly in the form of spoken voices. Command hallucinations, where voices tell people to hurt themselves or others, are an especially ominous sign: they can be difficult to resist and may precipitate violent actions.

The negative and cognitive symptoms are less dramatic but more pernicious. These can include a cluster called the 4 A's: autism (loss of interest in other people or the surroundings), ambivalence (emotional withdrawal), blunted affect (manifested by a bland and unchanging facial expression), and the cognitive problem of loose association (in which people join thoughts without clear logic, frequently jumbling words together into a meaningless word salad). Other common symptoms include a lack of spontaneity, impoverished speech, difficulty establishing rapport and a slowing of movement. Apathy and disinterest especially can cause friction between patients and their families, who may view these attributes as signs of laziness rather than manifestations of the illness.

When individuals with schizophrenia are evaluated with pencil-and-paper tests designed to detect brain injury, they show a pattern suggestive of widespread dysfunction. Virtually all aspects of brain operation, from the most basic sensory processes to the most complex aspects of thought are affected to some extent. Certain functions, such as the ability to form new memories either temporarily or permanently or to solve complex problems, may be particularly impaired. Patients also display difficulty solving the types of problems encountered in daily living, such as describing what friends are for or what to do if all the lights in the house go out at once. The inability to handle these common problems, more than anything else, accounts for the difficulty such individuals have in living independently. Overall, then, schizophrenia conspires to rob people of the very qualities they need to thrive in society: personality, social skills and wit.

New Treatment Possibilities
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DANIEL C. JAVITT and JOSEPH T. COYLE have studied schizophrenia for many years. Javitt is director of the Program in Cognitive Neuroscience and Schizophrenia at the Nathan Kline Institute for Psychiatric Research in Orangeburg, N.Y., and professor of psychiatry at the New York University School of Medicine. His paper demonstrating that the glutamate-blocking drug PCP reproduces the symptoms of schizophrenia was the second-most cited schizophrenia publication of the 1990s. Coyle is Eben S. Draper Professor of Psychiatry and Neuroscience at Harvard Medical School and also editor in chief of the Archives of General Psychiatry. Both authors have won numerous awards for their research. Javitt and Coyle hold independent patents for use of NMDA modulators in the treatment of schizophrenia, and Javitt has significant financial interests in Medifoods and Glytech, companies attempting to develop glycine and D-serine as treatments for schizophrenia.

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